The functional relationship between the ets gene of transforming leukemia virus, E26, and its cellular prototypes has been facilitated by structural comparisons at the nucleic acid and predicted protein levels. The nucleotide sequences of the chicken, mouse and human ets-I genes are over 95% identical to one another. The mammalian ets-2 genes from man and mouse encode for nearly identical amino acids and are over 90% conserved relative to the chicken ets-I gene. Alignment of the predicted ets proteins suggests that three domains exist. The domain closest to the carboxyl-termini is highly conserved in the predicted gene products from species ranging from human to Drosophila. The domain located at the aminoterminal end of the ets proteins is more divergent, being highly conserved only between the same gene isolated from different species (e.g., chicken ets-1 vs. human ETSI; mouse ets-2 vs. human ETS2). The central domain encoding the ets proteins is found to be most divergent, even between ets family genes of the same species. Thus, ets represents a family of genes whose members are diverging at variable rates. We have characterized the genomic structure of the human ETSI and ETS2 genes and find that while the ETSI locus consists of eight exons over 65 kb, the ETS2 gene contains 10 exons spanning 25 kb. The ETSI and ETS2 genes have transcript complexity due to multiple initiation sites, alternate splicing and multiple polyadenylation sites. They represent members of an increasingly large family of genes lacking TATA/CAAT promoter elements. ETSI reveals several highly conserved (near 100% identical) nucleic acid sequences. These may represent unique regulatory domains, binding a novel class of nuclear factors. Genes in addition to ETSI, ETS2, ERG, ELKI and ELK2 are present in the human genome. Thus far, we have defined two loci that appear to represent ETS2 pseudogenes and a new gene designated ERGB that, although related to ERG at the nucleotide level, has unique properties, including novel chromosome location and a more ubiquitous pattern of gene expression. Additional ETS-related genes are currently under analysis.